Pantothenic preparations and methods of obtaining the same



Patented Sept. 19, 1944 UNITED STATES "PATEN zissasss r OFFICE rmornamc raarsaarrons AND Marnons or oa'rammo 'rna ssMa Elmer J. Lawson, Hervey O.'Parke, and Leon A. 'Sweet, Detroit, Miclm-assignors to Parke, Davis & Company, Detroit, Mich, a corporation of Michigan No Application January 4, 1941, Serial No. 373,193

10Claims.

This invention relates to vitamin compositions and their preparation. invention relates to the preparation of pantothenic acid, a vitamin of the B complex occurring in liver and in yeast.

Pantothenic acid has the following structural formula,

on. on o and may be said to be the fl-alanide of an-dil vdro y-Bfi-dimethylbutyric acid. Pantothenic acid and its salts, almost all of which are very soluble in water, are eflective in stimulating the growth of yeast, bacteria and various other organisms.

According to the present invention, synthetic pantothenic acid preparations are obtained by condensing an dihydroxy as dimethylbu-.

tyramide with derivatives of fi-alanine such as the sodium salt, the ethyl ester or other derivatives in which the amino group of thefi-alanine is rendered reactive, i. e., in which the betaine character is suppressed by conversion of the COOH group into a functional derivative no longer having acidic properties, such derivatives generally include derivatives of the COOH, such as its salts, its nitrile, its esters, its amides, and the like. Derivatives of this sort are set forth in Houben-Weyl, Arbeitsmethoden der organischen Chemie, second edition, III,

- methylbutyramide condenses with derivatives of p-alanine such as the salts of ii-alanine with alkali metals and the esters of fl-alanine with aliphatic, or araliphatic alcohols or with phenols. The condensation is best conducted above room temperature, as from 50-l50 C., so that the ammonia formed may, readily escape.

The invention may be illustrated by the following examples.

More particularly, this Example 1 (a) Racemic a hydroxy as dimethyl butyrolactone may be prepared for example as described by Kohn and Neustadter, Monat'sh'. 39., 293 (1918). The lactone of melting point about 56 as thus obtained is suitable for use" without further purification. Y

(b) 75 grams of u-hydroxy-sp-dimethyl w butyrolactone is dissolved in about 400 cc. of liquid ammonia in an open vessel such as a 2 l. flask. The lactone dissolves immediately in the liquid ammonia with formation of a clear solution.

After standing OVel'llightyflll of the ammonia has evaporated to leave a crystalline solid. This solid is triturated with petroleum ether. collected on a funnel and washed several times with petroleum ether. The crude product thus obtained isrecrystallized from about ten times as much acetone. As thus obtained, the product, dl-a-ydihydmxy-pfi-dimethylbutyramide, has a melting point of 126,-i27 C. It is insoluble in petroleum ether and chloroform, somewhat soluble in acetone and quite soluble in alcohol. With aqueous sodium carbonate solution no ammonia is evolved, but with boiling aqueous sodium hydroxide solution ammonia is evolved. This shows that the substance is an amide rather than an ammonium salt. The yield is about grams.

A sample was analyzed with the following results: Calc. for C49.0%; Iii-8.90%; N9.52%;' found, C, 49.4%, 49.38%; H, 9.19%, 9.00%; N, 9.43%, 9.51%, I

Instead of using the racemic lactone as above to obtain the racemic amide, one may use either of the optically active forms of the lactone, thereby obtaining the optically active forms of theamide. Thus, the (-)-hydro ry-'p,p-dimethyl- 'y-butyrolactone'([a] =-50.4 in 2% aqueous solution), obtained from the more insoluble quinine salt in the resolution of the dl-lactone, yields the an dihydro iy #4 dimethyl butyramide having a melting point of 94 C. and [a] =+52 (in 2% methanolic solution); Similarly, the (+)=u-hydroxy-pfi-dimethyl-q-butyrolact'one (ial =approximately +50 in 2% aqueous solution), obtained as the more soluble quinine salt in the resolution of the dl-lactone. yields the -c. -dihydroxy-pfi-dimethyl-butyramide having a melting point of 94 C. and [a] of approximately 52. The optically active amides have in each case the same melting point, 94 C., and rotations of the same magnitude, but opposite sign. 1

Sample 2 p e tube and heated for about 3% hours at 100 C.'

Ammonia is evolved and the mixture melts to a still sirup. After cooling, the residue may be ulverized and used as the sodium salt of dl-pan- 4 thenic acid. Biological assays on the preparation obtained as described above show an activity corresponding to about a 70% yield oi the sodium salt of pantothenic acid, assuming that the racemic compound is only half. as active as the naturally occurring form. A

Instead of using the sodium salt of p-alanine in the above preparation, other alkali metal alanates such as potassium p-alanate, or esters such as the methyl ester or the ethyl ester of palanine may be used with analogous results.

Instead oi. using racemic ,-y-dihydroxy-p,fl-dimethylbutyramide in this preparation, the optical antipodes, i. e., -dihydroXy-fi-fi-dimethylbutyramide or (-)-a,-y-dihydroxy-fi fidimethylbutyramide may be used, thereby forming in thecase of the -amide, the active pantothenic acid as its sodium salt.

What we claim as our invention is:

1. The process which comprises treating a-hydroxy-pp-dimethyl- -butyrolactone with aminonia, and reacting the a,- -dihydroxy-p,fl-dimethyl butyramide thus formed with a com pound of the class consisting of an alkali metal salt of p-alanine and a lower aliphatic ester of p-alanine.

2. The process which comprises reacting a-hydroxy-pp-dimethylw-butyrolactone with liquid 7 ammonia, allowing the excess ammonia to evaporate, and reacting the sn-dihydromr-p p-dimethyl butyramide with a compound of the class consisting of an alkali metal salt 01' p-alanine and a lower aliphatic ester of p-alanine.

3. The process which comprise treating a-hydro fl.fl-dimethyl- -butyrclactone with ammonia, and heating the an-dihydroxy-pp-dimethylbutyramide thus produced with an alkali metal salt of p-alanine.

4. The process which comprises treating s-hydroxy-pfi-dimethyl-y-butyrolactone with ammonia, and heating the an-dihydroxy-fifi-dimethylbutyramide thus produced with the sodium salt of p-alanine.

5. The process which comprises treating s-hydroxy-,8,p-dimethyl- -butyrolactone with ammonia, and heating the ,'y-dihydroxy-p,p-dimethylbutyramide thus produced with a lower aliphatic ester of p-alanine.

6 The process which comprises reacting andihydro -fifi-dimethyl butyramide with a compound oi the class consisting of an alkali metal salt of p-alanine and a lower aliphatic ester of palanine.

'7. The process which comprises heating afldihydro -flfi-dimethylbutyramme with an alkali metal salt of p-alanine. A

8. The process which comprises heating agy- 

